There is now a body of evidence that metalloproteases (MP) are important in the uncontrolled breakdown of connective tissue, including proteoglycan and collagen, leading to resorption of the extracellular matrix. This is a feature of many pathological conditions, such as rheumatoid and osteoarthritis; corneal, epidermal, or gastric ulceration; tumor metastasis or invasion; periodontal disease; and bone disease. Normally these catabolic enzymes are tightly regulated at the level of their synthesis as well as at their level of extracellular activity through the action of specific inhibitors, such as alpha-2-macroglobulins and TIMPs (tissue inhibitors of metalloprotease), which form inactive complexes with the MP's.
Osteo- and Rheumatoid Arthritis (OA and RA respectively) are destructive diseases of articular cartilage characterized by localized erosion of the cartilage surface. Findings have shown that articular cartilage from the femoral heads of patients with OA, for example, had a reduced incorporation of radiolabeled sulfate over controls, suggesting that there must be an enhanced rate of cartilage degradation in OA (Mankin et al. J. Bone Joint Surg. 1970, 52A, 424–434). There are four classes of protein degradative enzymes in mammalian cells: serine, cysteine, aspartic, and metalloproteases. The available evidence supports that it is the metalloproteases that are responsible for the degradation of the extracellular matrix of articular cartilage in OA and RA. Increased activities of collagenases and stromelysin have been found in OA cartilage and the activity correlates with the severity of the lesion (Mankin et al. Arthritis Rheum. 1978, 21, 761–766, Woessner et al. Arthritis Rheum. 1983, 26, 63–68, and Woessner et al. Arthritis Rheum. 1984, 27, 305–312). In addition, aggrecanase has been identified as providing the specific cleavage product of proteoglycan found in RA and OA patients (Lohmander L. S. et al. Arthritis Rheum. 1993, 36, 1214–22).
Therefore, metalloproteases (MP) have been implicated as the key enzymes in the destruction of mammalian cartilage and bone. It can be expected that the pathogenesis of such diseases can be modified in a beneficial manner by the administration of MP inhibitors, and many compounds have been suggested for this purpose (see Wahl et al. Ann. Rep. Med. Chem. 1990, 25, 175–184, AP, San Diego).
Tumor necrosis factor-α (TNF-α) is a cell-associated cytokine that is processed from a 26kd precursor form to a 17kd soluble form. TNF-α has been shown to be a primary mediator in humans and in animals, of inflammation, fever, and acute phase responses, similar to those observed during acute infection and shock. Excess TNF-α has been shown to be lethal. There is now considerable evidence that blocking the effects of TNF-α with specific antibodies can be beneficial in a variety of circumstances including autoimmune diseases such as rheumatoid arthritis (Feldman et al, Lancet 1994, 344, 1105), non-insulin dependent diabetes melitus (Lohmander, L. S. et al. Arthritis Rheum. 1993, 36, 1214–22) and Crohn's disease (MacDonald et al. Clin. Exp. Immunol. 1990, 81, 301).
Compounds which inhibit the production of TNF-α are therefore of therapeutic importance for the treatment of inflammatory disorders. Recently, TNF-α converting enzyme (TACE), the enzyme responsible for TNF-α release from cells, were purified and sequenced (Black et al. Nature 1997, 385, 729; Moss et al. Nature 1997, 385, 733). This invention describes molecules that inhibit this enzyme and hence the secretion of active TNF-α from cells. These novel molecules provide a means of mechanism based therapeutic intervention for diseases including but not restricted to septic shock, haemodynamic shock, sepsis syndrome, post ischemic reperfusion injury, malaria, Crohn's disease, inflammatory bowel diseases, mycobacterial infection, meningitis, psoriasis, congestive heart failure, fibrotic diseases, cachexia, graft rejection, cancer, diseases involving angiogenesis, autoimmune diseases, skin inflammatory diseases, OA, RA, multiple sclerosis, radiation damage, hyperoxic alveolar injury, periodontal disease, HIV, and non-insulin dependent diabetes melitus.
Since excessive TNF-α production has been noted in several disease conditions also characterized by MMP-mediated tissue degradation, compounds which inhibit both MMPs and TNF-α production may also have a particular advantage in diseases where both mechanisms are involved.
It is desirable to find new compounds with improved pharmacological characteristics compared with known MMP and/or TACE inhibitors. For example, it is preferred to find new compounds with improved MMP and/or TACE inhibitory activity and selectivity for an MMP and/or TACE versus other metalloproteases. It is also desirable and preferable to find compounds with advantageous and improved characteristics in one or more of the following categories: (a) pharmaceutical properties; (b) dosage requirements; (c) factors which decrease blood concentration peak-to-trough characteristics; (d) factors that increase the concentration of active drug at the receptor; (e) factors that decrease the liability for clinical drug-drug interactions; (f) factors that decrease the potential for adverse side-effects; and (g) factors that improve manufacturing costs or feasibility.
EP 532,239 discloses 5-lipoxygenase inhibitors of the following formula:
wherein R4 can be a 6-membered monocyclic moiety containing 1–2 N; R5 is H or (1–4C)alkyl; A1 is a direct link or (1–3C)alkylene; X1 is O, S or imino; Ar is optionally substituted phenylene; and R1, R2, and R3 are groups as defined in EP 532,239.
WO 95/26957 describes endothelin receptor antagonists of the following formula:
wherein Q is a naphthyl or biphenyl group; W, X, Y and Z are independently selected from N or CR2; and A1, A2, A3 and R1 are groups as defined in WO 95/26957.
U.S. Pat. No. 5,332,759 describes compounds of the following formula:
wherein R3 is —SO2—NR6R7 or —CO—NR6R7; R6 and R7 have the same definition as R1 and R2; and R1 and R2 are groups as defined in U.S. Pat. No. 5,332,759.
U.S. Pat. No. 5,424,311 discloses intermediates of the following formula:
wherein V, W, Y and Z are CR1 or N; R2 and R5 are groups as defined in U.S. Pat. No. 5,424,311.
WO99/32117 illustrates acetylcholine receptor modulators of the following formula:
wherein A and B can be N; R1 and R2 can be H; D, E and G are linkers; J is NRcRf as defined in WO99/32117; R5 is —ORA, —OC(O)O—RA, —SRA, —NHC(O)RA, —NHSO2RA; and RA can be an optionally substituted aryl.
U.S. Pat. No. 6,242,455 depicts metalloproteinase inhibitors of the following formula:
wherein R1 and R2 can be H; R3 is W-V; W is a linker; V is H or a ring; and R4 is a residue as defined in U.S. Pat. No. 6,242,455.
WO 01/12611 describes metalloproteinase inhibitors of the following formula:
wherein X and Y are linkers; Ar1 is (C6–C10)aryl or (C2–C10)heteroaryl; and Z is (C6–C10)aryl, (C3–C8)cycloalkyl, (C3–C8)cycloalkyl(C1–C4)alkyl or (C2–C10)heteroaryl.
WO 01/96308 discloses AMPA receptor and kainite receptor inhibitors of the following formula:
wherein Q is NH, O or S; and R1 can be a dihydroxypyrimidyl capped group.
Compounds specifically described in the above mentioned patents or patent applications are not considered to be part of the present invention.
The compounds of the present invention act as inhibitors of MPs, in particular TACE, MMPs, and/or aggrecanase. These novel molecules are provided as anti-inflammatory compounds and cartilage protecting therapeutics.